Structural basis of the interaction between SETD2 methyltransferase and hnRNP L paralogs for governing co-transcriptional splicing.
Structural basis of the interaction between SETD2 methyltransferase and hnRNP L paralogs for governing co-transcriptional splicing.
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SETD2甲基转移酶和hnRNP L旁系同源物之间相互作用控制共转录剪接的结构基础
DOI：
10.1038/s41467-021-26799-3
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发表时间：
2021-11-08
影响因子：
16.6
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Bhattacharya S;Wang S;Reddy D;Shen S;Zhang Y;Zhang N;Li H;Washburn MP;Florens L;Shi Y;Workman JL;Li F
RNA识别基序(RRM)与核酸和蛋白质结合。在前mRNA处理的hnRNP蛋白中发现不止一个这样的结构域。虽然RRMS识别RNA的模式是已知的，但它们之间蛋白质相互作用的分子基础仍然不清楚。在这里，我们描述了hnRNP，L和LL之间的相互作用模式与甲基转移酶SETD2。我们证明了为了发生相互作用，在高度保守的SETD2片段中的一对亮氨酸将它们的侧链插入到由hnRNP L RRM2形成的疏水口袋中。值得注意的是，该结构还突出了RRM2可以与SETD2和RNA形成三元络合物。值得注意的是，突变SETD2中的亮氨酸对也会导致其与其他hnRNPs的相互作用减少。重要的是，SETD2-hnRNP L相互作用模式与其他相关蛋白质-蛋白质相互作用模式的相似性揭示了剪接调节子相互作用的保守设计。SETD2和hnRNP之间的相互作用L先前已经被证明参与了基因转录和基因加工的耦合。本文阐明了这种功能相互作用的分子基础，表明hnRNP L的RRM结构域具有与RNA和SETD2结合的非重叠结合界面。
The RNA recognition motif (RRM) binds to nucleic acids as well as proteins. More than one such domain is found in the pre-mRNA processing hnRNP proteins. While the mode of RNA recognition by RRMs is known, the molecular basis of their protein interaction remains obscure. Here we describe the mode of interaction between hnRNP L and LL with the methyltransferase SETD2. We demonstrate that for the interaction to occur, a leucine pair within a highly conserved stretch of SETD2 insert their side chains in hydrophobic pockets formed by hnRNP L RRM2. Notably, the structure also highlights that RRM2 can form a ternary complex with SETD2 and RNA. Remarkably, mutating the leucine pair in SETD2 also results in its reduced interaction with other hnRNPs. Importantly, the similarity that the mode of SETD2-hnRNP L interaction shares with other related protein-protein interactions reveals a conserved design by which splicing regulators interact with one another. Interaction between SETD2 and hnRNP L has previously been shown to be implicated in coupling gene transcription and mRNA processing. Here the authors elucidate the molecular basis of this functional interaction, showing that the RRM domain of hnRNP L possesses non-overlapping binding interfaces for engaging RNA and SETD2.